US7928093B2 - Amino-propanol derivatives - Google Patents
Amino-propanol derivatives Download PDFInfo
- Publication number
- US7928093B2 US7928093B2 US11/568,645 US56864505A US7928093B2 US 7928093 B2 US7928093 B2 US 7928093B2 US 56864505 A US56864505 A US 56864505A US 7928093 B2 US7928093 B2 US 7928093B2
- Authority
- US
- United States
- Prior art keywords
- phenyl
- formula
- methyl
- compound
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical class CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 230000002924 anti-infective effect Effects 0.000 claims description 6
- 230000002519 immonomodulatory effect Effects 0.000 claims description 6
- 239000003018 immunosuppressive agent Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000012678 infectious agent Substances 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 27
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000002054 transplantation Methods 0.000 abstract description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000007858 starting material Substances 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- RZTAMFZIAATZDJ-UHFFFAOYSA-N felodipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-UHFFFAOYSA-N 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 0 *C(CCN)(N)N Chemical compound *C(CCN)(N)N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
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- 239000012044 organic layer Substances 0.000 description 6
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- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 230000001506 immunosuppresive effect Effects 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- DZNVTMMIQNMYIV-QFBILLFUSA-N (2s,3r)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-ol Chemical compound CCCCCCCOC1=CC=C(CC[C@@](C)(N)[C@H](C)O)C=C1 DZNVTMMIQNMYIV-QFBILLFUSA-N 0.000 description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
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- 125000000623 heterocyclic group Chemical group 0.000 description 4
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- -1 p-methoxybenzyl Chemical group 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- SLSBCIOYPJDNRK-HSZRJFAPSA-N tert-butyl n-[(2r)-4-(4-heptoxyphenyl)-2-methyl-1-oxobutan-2-yl]carbamate Chemical compound CCCCCCCOC1=CC=C(CC[C@@](C)(NC(=O)OC(C)(C)C)C=O)C=C1 SLSBCIOYPJDNRK-HSZRJFAPSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101100236683 Homo sapiens MBTPS1 gene Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000001861 immunosuppressant effect Effects 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- CAHXRDGRZIUFGA-DNQXCXABSA-N (1r,2r)-2-amino-4-(4-heptoxyphenyl)-2-methyl-1-phenylbutan-1-ol Chemical compound C1=CC(OCCCCCCC)=CC=C1CC[C@@](C)(N)[C@H](O)C1=CC=CC=C1 CAHXRDGRZIUFGA-DNQXCXABSA-N 0.000 description 2
- CAHXRDGRZIUFGA-BJKOFHAPSA-N (1s,2r)-2-amino-4-(4-heptoxyphenyl)-2-methyl-1-phenylbutan-1-ol Chemical compound C1=CC(OCCCCCCC)=CC=C1CC[C@@](C)(N)[C@@H](O)C1=CC=CC=C1 CAHXRDGRZIUFGA-BJKOFHAPSA-N 0.000 description 2
- FFFYHOOQEQXABT-IIBYNOLFSA-N (2r,3r)-3-amino-3-methyl-5-(6-pentoxynaphthalen-2-yl)pentan-2-ol Chemical compound C1=C(CC[C@@](C)(N)[C@@H](C)O)C=CC2=CC(OCCCCC)=CC=C21 FFFYHOOQEQXABT-IIBYNOLFSA-N 0.000 description 2
- MSSGDCFUAIHBCB-XMSQKQJNSA-N (2r,3r)-3-amino-3-methyl-5-[4-(4-phenylbutoxy)phenyl]pentan-2-ol Chemical compound C1=CC(CC[C@@](C)(N)[C@H](O)C)=CC=C1OCCCCC1=CC=CC=C1 MSSGDCFUAIHBCB-XMSQKQJNSA-N 0.000 description 2
- VHBJWKKJUQNMLK-FQRUVTKNSA-N (2r,3r)-3-amino-3-methyl-5-[4-[2-(4-phenylphenyl)ethoxy]phenyl]pentan-2-ol Chemical compound C1=CC(CC[C@@](C)(N)[C@H](O)C)=CC=C1OCCC1=CC=C(C=2C=CC=CC=2)C=C1 VHBJWKKJUQNMLK-FQRUVTKNSA-N 0.000 description 2
- DZNVTMMIQNMYIV-VQIMIIECSA-N (2r,3r)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-ol Chemical compound CCCCCCCOC1=CC=C(CC[C@@](C)(N)[C@@H](C)O)C=C1 DZNVTMMIQNMYIV-VQIMIIECSA-N 0.000 description 2
- DZNVTMMIQNMYIV-APWZRJJASA-N (2r,3s)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-ol Chemical compound CCCCCCCOC1=CC=C(CC[C@](C)(N)[C@@H](C)O)C=C1 DZNVTMMIQNMYIV-APWZRJJASA-N 0.000 description 2
- FFFYHOOQEQXABT-HRAATJIYSA-N (2s,3r)-3-amino-3-methyl-5-(6-pentoxynaphthalen-2-yl)pentan-2-ol Chemical compound C1=C(CC[C@@](C)(N)[C@H](C)O)C=CC2=CC(OCCCCC)=CC=C21 FFFYHOOQEQXABT-HRAATJIYSA-N 0.000 description 2
- MSSGDCFUAIHBCB-PGRDOPGGSA-N (2s,3r)-3-amino-3-methyl-5-[4-(4-phenylbutoxy)phenyl]pentan-2-ol Chemical compound C1=CC(CC[C@@](C)(N)[C@@H](O)C)=CC=C1OCCCCC1=CC=CC=C1 MSSGDCFUAIHBCB-PGRDOPGGSA-N 0.000 description 2
- YHLICHWHHWVEKT-WMZHIEFXSA-N (2s,3r)-3-amino-3-methyl-5-[4-(5-phenylpentoxy)phenyl]pentan-2-ol Chemical compound C1=CC(CC[C@@](C)(N)[C@@H](O)C)=CC=C1OCCCCCC1=CC=CC=C1 YHLICHWHHWVEKT-WMZHIEFXSA-N 0.000 description 2
- VHBJWKKJUQNMLK-RXFWQSSRSA-N (2s,3r)-3-amino-3-methyl-5-[4-[2-(4-phenylphenyl)ethoxy]phenyl]pentan-2-ol Chemical compound C1=CC(CC[C@@](C)(N)[C@@H](O)C)=CC=C1OCCC1=CC=C(C=2C=CC=CC=2)C=C1 VHBJWKKJUQNMLK-RXFWQSSRSA-N 0.000 description 2
- DZNVTMMIQNMYIV-LPHOPBHVSA-N (2s,3s)-3-amino-5-(4-heptoxyphenyl)-3-methylpentan-2-ol Chemical compound CCCCCCCOC1=CC=C(CC[C@](C)(N)[C@H](C)O)C=C1 DZNVTMMIQNMYIV-LPHOPBHVSA-N 0.000 description 2
- RXZWSZLLBRXZPY-FIWHBWSRSA-N (3r)-4-amino-6-(4-heptoxyphenyl)-4-methylhex-1-yn-3-ol Chemical compound CCCCCCCOC1=CC=C(CCC(C)(N)[C@H](O)C#C)C=C1 RXZWSZLLBRXZPY-FIWHBWSRSA-N 0.000 description 2
- KBIQEQIRXQQVKG-WOJBJXKFSA-N (3r,4r)-4-amino-6-(4-heptoxyphenyl)-4-methylhexan-3-ol Chemical compound CCCCCCCOC1=CC=C(CC[C@@](C)(N)[C@H](O)CC)C=C1 KBIQEQIRXQQVKG-WOJBJXKFSA-N 0.000 description 2
- KBIQEQIRXQQVKG-VQTJNVASSA-N (3s,4r)-4-amino-6-(4-heptoxyphenyl)-4-methylhexan-3-ol Chemical compound CCCCCCCOC1=CC=C(CC[C@@](C)(N)[C@@H](O)CC)C=C1 KBIQEQIRXQQVKG-VQTJNVASSA-N 0.000 description 2
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
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- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
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- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
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- 230000001537 neural effect Effects 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
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- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960001302 ridaforolimus Drugs 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 125000002345 steroid group Chemical group 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 231100000617 superantigen Toxicity 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- XKDANMLSJTYUPV-MRXNPFEDSA-N tert-butyl n-[(2r)-1-hydroxy-4-(4-hydroxyphenyl)-2-methylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@](C)(CO)CCC1=CC=C(O)C=C1 XKDANMLSJTYUPV-MRXNPFEDSA-N 0.000 description 1
- NIXRTURDUYSHSR-HSZRJFAPSA-N tert-butyl n-[(2r)-4-(4-heptoxyphenyl)-1-hydroxy-2-methylbutan-2-yl]carbamate Chemical compound CCCCCCCOC1=CC=C(CC[C@](C)(CO)NC(=O)OC(C)(C)C)C=C1 NIXRTURDUYSHSR-HSZRJFAPSA-N 0.000 description 1
- ULEDSCPNPUJZFG-RCZVLFRGSA-N tert-butyl n-[(3r,4r)-1-(4-heptoxyphenyl)-4-hydroxy-3-methylhexan-3-yl]carbamate Chemical compound CCCCCCCOC1=CC=C(CC[C@@](C)(NC(=O)OC(C)(C)C)[C@H](O)CC)C=C1 ULEDSCPNPUJZFG-RCZVLFRGSA-N 0.000 description 1
- DCNSDVJKUPISKS-NLGDKJDOSA-N tert-butyl n-[(3r,4r)-4-[bis[(2-methylpropan-2-yl)oxy]phosphoryloxy]-1-(4-heptoxyphenyl)-3-methylpentan-3-yl]carbamate Chemical compound CCCCCCCOC1=CC=C(CC[C@@](C)(NC(=O)OC(C)(C)C)[C@@H](C)OP(=O)(OC(C)(C)C)OC(C)(C)C)C=C1 DCNSDVJKUPISKS-NLGDKJDOSA-N 0.000 description 1
- QKYWEFZFDKAADA-YADARESESA-N tert-butyl n-[(3r,4s)-1-(4-heptoxyphenyl)-4-hydroxy-3-methylpentan-3-yl]carbamate Chemical compound CCCCCCCOC1=CC=C(CC[C@@](C)(NC(=O)OC(C)(C)C)[C@H](C)O)C=C1 QKYWEFZFDKAADA-YADARESESA-N 0.000 description 1
- QKYWEFZFDKAADA-CYFREDJKSA-N tert-butyl n-[(3s,4s)-1-(4-heptoxyphenyl)-4-hydroxy-3-methylpentan-3-yl]carbamate Chemical compound CCCCCCCOC1=CC=C(CC[C@](C)(NC(=O)OC(C)(C)C)[C@H](C)O)C=C1 QKYWEFZFDKAADA-CYFREDJKSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical group [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- BICRTLVBTLFLRD-PTWUADNWSA-N voclosporin Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C=C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O BICRTLVBTLFLRD-PTWUADNWSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/094—Esters of phosphoric acids with arylalkanols
Definitions
- the present invention relates to amino-propanol derivatives, process for their production, their uses and pharmaceutical compositions containing them.
- Alkyl or alkyl moiety may be straight or branched chain, e.g. methyl, ethyl, propyl, iso-propyl or butyl.
- Alkenyl may be e.g. vinyl.
- Cycloalkyl may be e.g. C 3-6 cycloalkyl.
- Acyl may be a residue W—CO wherein W is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl or phenylC 1-4 alkyl.
- Halogen may be F, Cl or Br, preferably F or Cl.
- Heteroaryl may be a 5 to 8 membered aromatic ring comprising 1 to 4 heteroatoms selected from N, O and S, e.g. pyridyl, pyrimidinyl, pyrazinyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, thiophenyl, isothiazolyl, pyrrolyl, imidazolyl, or pyrazolyl.
- N, O and S e.g. pyridyl, pyrimidinyl, pyrazinyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, thiophenyl, isothiazolyl, pyrrolyl, imidazolyl, or pyrazolyl.
- heterocyclic residue is meant a 3 to 8, preferably 5 to 8, membered saturated or unsaturated heterocyclic ring comprising e.g. tetrahydrofuryl, tetrahydropyranyl, aziridinyl, piperidinyl, pyrrolidinyl, piperazinyl.
- Compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. inorganic acids, such as hydrochloride, hydrobromide or sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or benzenesulfonate salts.
- inorganic acids such as hydrochloride, hydrobromide or sulfate
- organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or benzenesulfonate salts.
- Compounds of formula I and their salts, in hydrate or solvate form are also part of the invention.
- the compounds of formula I When the compounds of formula I have asymmetric centers in the molecule, various optical isomers are obtained.
- the present invention also encompasses enantiomers, racemates, diastereoisomers and mixtures thereof.
- the central carbon atom bearing R 1 , R 3 and NR 4 R 5 may have the R or S configuration.
- Compounds having the following 3-dimensional configuration are generally preferred:
- the present invention embraces cis-compounds, trans-compounds and mixtures thereof. Similar considerations apply in relation to starting materials exhibiting asymmetric carbon atoms or unsaturated bonds as mentioned above, e.g. compounds of formula II, or III as indicated below.
- R 1 is CH 3 or CH 2 —OH
- R 3 is a residue of formula —CH(R 8 )(OH) or of formula —CH(R 8 )(OPO(OR 9 )(OR 10 ))
- each of R 4 and R 5 is hydrogen
- X is O or a bond
- R 7 is hydrogen, phenyl or thiophenyl
- R 8 is methyl, ethyl, ethynyl or phenyl
- R 9 is H
- R 10 is H.
- the present invention also includes a process for the preparation of a compound of formula I which process comprises
- R 1 , R 2 and R 5 are as defined above
- R′ 3 is —Y(R 8 )(OH) wherein Y and R 8 are as defined above
- R 14 is an amino protecting group
- R 1 , R 2 , R 14 and R 5 are as defined above, R′ 3 is a residue of formula (e′)
- R′ 9 and R′ 10 are as defined above, and each of R′ 9 and R′ 10 , is a hydrolysable or hydrogenolysable group or R′ 9 and R′ 10 form together a divalent bridging residue optionally fused to a ring (e.g. benzene ring), and, where required, converting the compounds of formula I obtained in free form into the desired salt form, or vice versa.
- a ring e.g. benzene ring
- Removal of protecting group may be carried out in accordance with methods known in the art.
- the removal of the amino protecting groups may conveniently be performed according to methods known in the art, e.g. by hydrolysis, e.g. in an acidic medium, for example using hydrochloric acid.
- Examples of protecting groups for amino groups are e.g. as disclosed in “Protective Groups in Organic Synthesis” T. W. Greene, J. Wiley & Sons NY, 2 nd ed., chapter 7, 1991, and references therein, e.g.
- benzyl p-methoxybenzyl, methoxymethyl, tetrahydro-pyranyl, trialkylsilyl, acyl, tert.-butoxy-carbonyl, benzyloxycarbonyl, 9-fluorenyl methoxy carbonyl, trifluoroacetyl, and the like.
- the present invention also includes a process for the preparation of a compound of formula II, wherein X is O or S, which process comprises alkylating a compound of formula IV
- R 1 , R 3 ′, R 4 ′, R 5 are as defined above, and R′ 2 is a radical of formula (a′) or (b′) or (c′) or (d′)
- Alkylation of the compounds of formula IV may be performed according to methods known in the art, e.g. by nucleophilic substitution, e.g. by reaction with an alkylating agent R 6 —X 3 wherein X 3 is mesylate, tosylate, triflate, nosylate or an halogen, e.g. chloride, bromide or iodide.
- the alkylation may also be carried out by following the Mitsunobu protocol (e.g. as disclosed in Hughes, Organic Preparations and Procedures International 28, 127-64, 1996 or D. L. Hughes, Org. React. 42, 335, 1992), in solution or on solid phase support synthesis, e.g. by attaching the compound of formula IV to a resin.
- either triphenyl-phosphine or e.g. diethyl azocarboxylate bound to a resin, e.g. polystyrene can be used.
- Methods A, B, G and H are known in the art, and may be performed e.g. as disclosed in K. Deutschending et al, Synthesis 2003, 1667.
- M may be any metal or metal salt used in addition reactions to aldehydes known in the art, e.g. MgCl, MgBr, Mgl, Li, Zn, Cu.
- PG means protecting group
- reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO 3 (saturated aqueous solution).
- aqueous phase is extracted with AcOEt (3 times).
- the combined organic layers are dried (Na 2 SO 4 ) and concentrated under reduced pressure.
- Column chromatography eluting with 0% ⁇ 40% AcOEt in heptane gives ⁇ (R)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-1-hydroxymethyl-1-methyl-propyl ⁇ -carbamic acid tert-butyl ester as a colourless oil.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound is purified by digeration with Et 2 O and is obtained as its hydrochloride salt.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 5 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared analogously to Example 1 using appropriate starting materials.
- the product is purified by RP-HPLC (ZORBAX Extend C-18) eluting with 5% ⁇ 95% CH 3 CN in H 2 O (+0.1% TFA).
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound is lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 9 using appropriate starting materials.
- the product is purified by RP-HPLC (ZORBAX Extend C-18) eluting with 5% ⁇ 95% CH 3 CN in H 2 O (+0.1% TFA) to give the title compound.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound is lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound is lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 1 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 18 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the title compound is prepared as described in Example 18 using appropriate starting materials.
- the compound was lyophilized from dioxane to give a white, amorphous powder.
- the compounds of formula I in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, e.g. lymphocyte recirculation modulating properties, e.g. as indicated in in vitro and in vivo tests and are therefore indicated for therapy.
- useful pharmacological properties e.g. lymphocyte recirculation modulating properties, e.g. as indicated in in vitro and in vivo tests and are therefore indicated for therapy.
- the compounds of formula I have binding affinity to individual human S1P receptors as determined in following assays:
- S1P Sphingosine-1-phosphate
- Agonist activities of compounds are tested on the human S1P receptors EDG-1 (S1P 1 ), EDG-3 (S1P 3 ), EDG-5 (S1P 2 ), EDG-6 (S1P 4 ) and EDG-8 (S1P 5 ).
- Functional receptor activation is assessed by quantifying compound induced GTP [ ⁇ - 35 S] binding to membrane protein prepared from transfected CHO or RH7777 cells stably expressing the appropriate human S1P receptor.
- the assay technology used is SPA (scintillation proximity based assay).
- DMSO dissolved compounds are serially diluted and added to SPA-bead (Amersham-Pharmacia) immobilised SIP receptor expressing membrane protein (10-20 ⁇ g/well) in the presence of 50 mM Hepes, 100 mM NaCl, 10 mM MgCl 2 , 10 ⁇ M GDP, 0.1% fat free BSA and 0.2 nM GTP [ ⁇ - 35 S] (1200 Ci/mmol). After incubation in 96 well microtiterplates at RT for 120 min, unbound GTP [ ⁇ - 35 S] is separated by a centrifugation step. Luminescence of SPA beads triggered by membrane bound GTP [ ⁇ - 35 S] is quantified with a TOPcount plate reader (Packard). EC 50 s are calculated using standard curve fitting software. In this assay, the compounds of formula I have a binding affinity to S1P 1 receptor ⁇ 50 nM.
- a compound of formula I or the vehicle is administered orally by gavage to rats.
- Tail blood for hematological monitoring is obtained on day ⁇ 1 to give the baseline individual values, and at 2, 6, 24, 48 and 72 hours after application.
- the compounds of formula I deplete peripheral blood lymphocytes when administered at a dose of 0.03 to 3 mg/kg. For example, following results are obtained: depletion of peripheral blood lymphocytes by more than 50%.
- Example 1 0.07 mg/kg p.o. after 6 h
- Example 12 0.4 mg/kg p.o. after 6 h
- Example 13 0.5 mg/kg p.o. after 6 h
- Example 14 0.1 mg/kg p.o. after 6 h
- Example 15 0.6 mg/kg p.o. after 6 h
- Example 17 0.2 mg/kg p.o. after 6 h
- the compounds of formula I are, therefore, useful in the treatment and/or prevention of diseases or disorders mediated by lymphocytes interactions, e.g. in transplantation, such as acute or chronic rejection of cell, tissue or organ allo- or xenografts or delayed graft function, graft versus host disease, autoimmune diseases, e.g.
- rheumatoid arthritis systemic lupus erythematosus, hashimoto's thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or II and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves opthalmopathy, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inflammatory diseases optionally with underlying aberrant reactions, e.g.
- inflammatory bowel disease Crohn's disease or ulcerative colitis
- intrinsic asthma inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, ischemia/reperfusion injury, e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, traumatic shock, angiogenesis, Alzheimer's disease, cancer, e.g.
- T cell lymphomas or T cell leukemias infectious diseases, e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, chronic bacterial infection, or senile dementia.
- infectious diseases e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, chronic bacterial infection, or senile dementia.
- cell, tissue or solid organ transplants include e.g. pancreatic islets, stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus.
- the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired.
- An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
- Suitable unit dosage forms for oral administration comprise from ca. 0.1 to 50 mg active ingredient.
- the compounds of formula I may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form.
- Pharmaceutical compositions comprising a compound of formula I in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
- the compounds of formula I wherein R 3 is a radical of formula (d), i.e. compounds of formula I.1, are administered perorally, and preferably have the R,R configuration as shown in FIG. 1.
- the compounds of formula I wherein R 3 is a radical of formula (e), i.e. compounds of formula I.2 are administered parenterally, and preferably have the S,R configuration as shown in FIG. 1.
- FIG. 1 Preferred Configuration of Compounds of Formula I.1 and I.2
- the compounds of formula I may be administered in free form or in pharmaceutically acceptable salt form e.g. as indicated above.
- Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
- the present invention further provides:
- the compounds of formula I may be administered as the sole active ingredient or in conjunction with, e.g. as an adjuvant to, other drugs e.g. immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g. for the treatment or prevention of alio- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or a chemotherapeutic agent, e.g a malignant cell anti-proliferative agent.
- the compounds of formula I may be used in combination with a calcineurin inhibitor, e.g. cyclosporin A, FK 506 or ISA TX 247; a mTOR inhibitor, e.g.
- rapamycin 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus 7 or biolimus 9; an ascomycin having immunosuppressive properties, e.g. ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or a salt thereof, e.g.
- immunosuppressive monoclonal antibodies e.g. monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40. CD45, CD58, CD80, CD86 or their ligands; other immunomodulatory compounds, e.g. a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g.
- CTLA4Ig for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or a chemotherapeutic agent, e.g. paclitaxel, gemcitabine, cisplatinum, doxorubicin or 5-fluorouracil; or an anti-infectious agent.
- adhesion molecule inhibitors e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists
- a chemotherapeutic agent e.g. paclitaxel, gemcitabine, cisplatinum, doxorubicin or 5-fluorouracil
- an anti-infectious agent e.g. paclitaxel, gemcitabine, cisplatinum, doxorubicin or 5-fluorouraci
- the compounds of formula I are administered in conjunction with other immuno-suppressive/immunomodulatory, anti-inflammatory chemotherapeutic or anti-infectious therapy
- dosages of the co-administered immunosuppressant, immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infectious compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth.
- the present invention provides in a yet further aspect:
- co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
- pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
- fixed combination means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
- non-fixed combination means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
- cocktail therapy e.g. the administration of 3 or more active ingredients.
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GBGB0411929.3A GB0411929D0 (en) | 2004-05-27 | 2004-05-27 | Organic compounds |
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PCT/EP2005/005685 WO2005118523A1 (en) | 2004-05-27 | 2005-05-25 | Amino-propanol derivatives |
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US7928093B2 true US7928093B2 (en) | 2011-04-19 |
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EP (1) | EP1753712B1 (zh) |
JP (1) | JP4490482B2 (zh) |
KR (1) | KR100837897B1 (zh) |
CN (1) | CN100575335C (zh) |
AT (1) | ATE431333T1 (zh) |
AU (1) | AU2005250112B2 (zh) |
BR (1) | BRPI0511610A (zh) |
CA (1) | CA2562332A1 (zh) |
DE (1) | DE602005014473D1 (zh) |
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GB (1) | GB0411929D0 (zh) |
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AU2004234067B2 (en) * | 2003-04-30 | 2008-02-28 | Novartis Ag | Aminopropanol derivatives as sphingosine-1-phosphate receptor modulators |
WO2005041899A2 (en) | 2003-11-03 | 2005-05-12 | University Of Virginia Patent Foundation | Orally available sphingosine 1-phosphate receptor agonists and antagonists |
CN101905023B (zh) * | 2004-07-16 | 2012-07-11 | 杏林制药株式会社 | 有效的医药使用方法及与副作用发生的防御相关的方法 |
EP1781595A1 (en) | 2004-08-13 | 2007-05-09 | Praecis Pharmaceuticals Inc. | Methods and compositions for modulating sphingosine-1-phosphate (s1p) receptor activity |
US7795472B2 (en) * | 2004-10-12 | 2010-09-14 | Kyorin Pharmaceutical Co., Ltd. | Process for producing 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride and hydrates thereof, and intermediates in the production thereof |
MX2007006706A (es) | 2004-12-06 | 2007-10-18 | Univ Virginia | Analogos de esfingosina 1-fosfato amida de arilo. |
US8048928B2 (en) * | 2005-10-07 | 2011-11-01 | Kyorin Pharmaceutical Co., Ltd. | Therapeutic agent for treating liver disease containing 2-amino-1,3-propanediol derivative as active ingredient, and method for treating liver disease |
RU2008134702A (ru) | 2006-01-27 | 2010-03-10 | Юниверсити Оф Вирждиния Пэтент Фаундейшн (Us) | Способ лечения невропатической боли |
TWI389683B (zh) * | 2006-02-06 | 2013-03-21 | Kyorin Seiyaku Kk | A therapeutic agent for an inflammatory bowel disease or an inflammatory bowel disease treatment using a 2-amino-1,3-propanediol derivative as an active ingredient |
EP1987013A1 (en) * | 2006-02-09 | 2008-11-05 | University Of Virginia Patent Foundation | Bicyclic sphingosine 1-phosphate analogs |
NZ574011A (en) * | 2006-08-08 | 2011-10-28 | Kyorin Seiyaku Kk | Aminophosphoric acid ester derivative and s1p receptor modulator containing the same as active ingredient |
SG174029A1 (en) | 2006-08-08 | 2011-09-29 | Kyorin Seiyaku Kk | Aminoalcohol derivative and immunosuppressant containing the same as active ingredient |
NZ576893A (en) | 2006-11-21 | 2012-01-12 | Univ Virginia Patent Found | Tetralin analogs having sphingosine 1-phosphate agonist activity |
CA2669124A1 (en) | 2006-11-21 | 2008-05-29 | University Of Virginia Patent Foundation | Benzocycloheptyl analogs having sphingosine 1-phosphate receptor activity |
EP2099741A2 (en) | 2006-11-21 | 2009-09-16 | University Of Virginia Patent Foundation | Hydrindane analogs having sphingosine 1-phosphate receptor agonist activity |
WO2008124210A1 (en) * | 2007-02-14 | 2008-10-16 | Emory University | Methods and compositions for treating or preventing infection using leukocyte sequestration agents |
WO2009099174A1 (ja) | 2008-02-07 | 2009-08-13 | Kyorin Pharmaceutical Co., Ltd. | アミノアルコール誘導体を有効成分とする炎症性腸疾患の治療剤又は予防剤 |
AR074062A1 (es) * | 2008-10-31 | 2010-12-22 | Lexicon Pharmaceuticals Inc | Agonistas del receptor s1p para el tratamiento de la malaria cerebral y forma farmaceutica |
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EP0778263A1 (en) | 1994-08-22 | 1997-06-11 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzene compound and medicinal use thereof |
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WO2002076995A2 (en) | 2001-03-26 | 2002-10-03 | Novartis Ag | 2-amino-propanol derivatives |
US20060211656A1 (en) * | 2003-04-30 | 2006-09-21 | Rainer Albert | Aminopropanol derivatives as sphingosine-1-phosphate receptor modulators |
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KR100551931B1 (ko) * | 1997-04-04 | 2006-02-16 | 미츠비시 웰파마 가부시키가이샤 | 2-아미노프로판-1,3-디올 화합물, 이것의 의약으로서의 용도 및 합성 중간체 |
JP4166218B2 (ja) * | 2002-09-13 | 2008-10-15 | ノバルティス アクチエンゲゼルシャフト | アミノ−プロパノール誘導体 |
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EP0778263A1 (en) | 1994-08-22 | 1997-06-11 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzene compound and medicinal use thereof |
US5948820A (en) * | 1994-08-22 | 1999-09-07 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzene compound and pharmaceutical use thereof |
WO2002076995A2 (en) | 2001-03-26 | 2002-10-03 | Novartis Ag | 2-amino-propanol derivatives |
US20060211656A1 (en) * | 2003-04-30 | 2006-09-21 | Rainer Albert | Aminopropanol derivatives as sphingosine-1-phosphate receptor modulators |
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KR20070015439A (ko) | 2007-02-02 |
PT1753712E (pt) | 2009-08-06 |
PL1753712T3 (pl) | 2009-10-30 |
DE602005014473D1 (en) | 2009-06-25 |
AU2005250112A1 (en) | 2005-12-15 |
JP4490482B2 (ja) | 2010-06-23 |
JP2008500302A (ja) | 2008-01-10 |
MXPA06013624A (es) | 2007-02-28 |
ATE431333T1 (de) | 2009-05-15 |
RU2006146215A (ru) | 2008-07-10 |
US20070225260A1 (en) | 2007-09-27 |
CA2562332A1 (en) | 2005-12-15 |
WO2005118523A1 (en) | 2005-12-15 |
BRPI0511610A (pt) | 2008-01-02 |
ES2327250T3 (es) | 2009-10-27 |
GB0411929D0 (en) | 2004-06-30 |
CN1946679A (zh) | 2007-04-11 |
CN100575335C (zh) | 2009-12-30 |
KR100837897B1 (ko) | 2008-06-13 |
AU2005250112B2 (en) | 2009-01-08 |
EP1753712B1 (en) | 2009-05-13 |
EP1753712A1 (en) | 2007-02-21 |
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